2-aminophenyl-acetamides



United States Patent 3,310,582 Z-AMINOPHENYL-ACETAMIDES George de Stevens, Summit, N.J., assignor t0 Ciba Corporation, New York, N.Y., a corporation of Delaware No Drawing. Filed Nov. 26, 1963, Ser. No. 326,254 14 Claims. (Cl. 260-559) This is a continuation-in-part of application Ser. No. 120,179, filed June 28, 1961 (now Patent No. 3,157,642).

The present invention concerns certain 2,3,4,5-tetrahydro-lH-I,3-benzodiazepin-4-ones. More especially, it relates to l-R-lower alkyl-3-R -5-R -2,3,4,5-tetrahydrolH-l,3-benzodiazepin-4-ones, in which R represents a carbocyclic aryl or a heterocyclic aryl radical, R represents an aliphatic, a carbocyclic aryl or a carbocyclic aryl-aliphatic radical, and R stands for hydrogen or an aliphatic radical, and in which the benzonucleus is substituted, salts, N-oxides or quaternary ammonium compounds thereof. The compounds of this invention may, therefore, be represented by the formula in which Ph represents a substituted 1,2-phenylene radical, R represents a carbocyclic aryl or a heterocyelic aryl radical, the letter It stands for one of the numbers 1, 2 or 3, R stands for an aliphatic, a carbocyclic aryl or a car bocyclic aryl-aliphatic radical, and R represents hydrogen or an aliphatic radical, salts, N-oxides or quaternary ammorium compounds thereof.

An R-lower alkyl group, which group is represented by -(C H )R in the above formula, is more especially a monocyclic carbocyclic-lower alkyl group, in which the monocyclic carbocyclic aryl group stands for phenyl, as well as substituted phenyl, in which one or more than one of the same or of different substituents may be attached to any of the positions available for substitution. Substituents are, for example, lower alkyl, e.g. methyl, ethyl, n-propyl, isopr-opyl, n-butyl, tertiary butyl and the like, etherified hydroxyl, particularly lower alkoxy, e.g. methoxy, ethoxy, n-propyloxy, iso-propyloxy, n-butyloxy and the like, lower alkenyloxy, e.g. allyloxy and the like, lower alkylenedio-xy, e.g. methylenedioxy and the like, or any other etherified hydroxyl group, esterified hydroxyl, particularly halogeno, e.g. fluoro, chloro, bromo and the like, or other esterified hydroxyl, etherified mercapto, particularly lower alkyl-mercapto, e.g. methylmercapto, ethylmercapto and the like, or any other etherified mercapto group, nitro, tertiary amino, particularly N,N-dilower alkyl-amino, e.g. N,N-dimethylamino, N,N-cliethylamino and the like, or any other amino group, trifiuoromethyl or any other suitable substituent. Substituted phenyl groups are, therefore, (lower alkyl)-phenyl, e.g. B-methyl-phenyl, 4-methyl-phenyl, 2,4,5- trimethyl-phenyl, 4-ethyl-phenyl, 4-isopropyl-phenyl and the like, (etherified hydr-oXy)-phenyl, particularly (lower alkoXy)-phenyl, e.g. 4methoXy-p'henyl, 3,4-dimethoxy-phenyl, 3,4,5-trimethoxy-phenyl, 4-ethoXy-pheny1 and the like, (lower alkenyloXy)-phenyl, e.g. 2-ally1oXy-phenyl and the like, (lower alkylenedioxy)-phenyl, e.g. 3,4-methylenedioxyphenyl and the like, or any other (etherified hydroxy)- phenyl group, (esterified hydroXy)-phenyl, particularly '(halogeno)-phenyl, e.g. 4-fiuoro-phenyl, 4-chloro-pheny1, 3,4-dichloro-phenyl, 2-bron1o-phenyl and the like, or any other (esterified hydroXy)-p henyl, (etherified mercapto)- phenyl, particularly (lower alkyl-mercapto)phenyl, e.g.

4-methylrnercapto-phenyl, 4-.ethylmercapto-pheny1 and the ice like, or any other (etherified mercapto)-phenyl, (nitro)- phenyl, e.g. 4-nitro-phenyl and the like, (teritary amino)- phenyl, particularly (N,N-di-lower alkylamino)-phenyl, e.g. 4-N,Ndimethylamino-phenyl and the like, or any other (amino)-phenyl, (trifluoromethyl) -phenyl, e.g. 4 trifluoromet-hyl-phenyl and the like, or any other suitably substituted phenyl group.

The group R in the R-lower alkyl substituent may also represent a bicyclic carbocyclic aryl group, e.g. l-naphthyl or Z-naphthyl, as well as substituted naphthyl, such as (lower alkyl)-naphthyl, (etherified hydroxy)-naphthy1, particularly (lower alkoXy)-naphthyl, (lower alkenyloxy)- naphthyl or (lower alkylenedioxy) -naphthyl and the like, (esterified hydroxy)-naphthyl, particularly (halogeno)- naphthyl and the like, (etherified mercapto)-naphthyl,

particularly (lower alkyl-mercapto)-naphthyl and the like,

(nitro)-naphthyl, (tertiary amino)-naphthyl, particularly (N,N-di-lower alkyl-amino)-naphthyl and the like, (trifluoromethyl)-naphthyl and the like, or any other substituted naphthyl group; in the above-mentioned substituted naphthyl radicals, substituents are analogous to those in the substituted phenyl groups.

The group R in an R-lower alkyl group may also represent a heterocyclic, particularly monocyclic heterocyclic, aryl radical, which may be represented by pyridyl, e.g. 2-pyridyl, B-pyridyl or 4-pyridyl, or substituted pyridyl, such as (lower alkyl) -pyridyl, (lower alkoxy)-pyridyl, (halogeno)-pyridyl and the like, in which lower alkyl, lower alkoxy, or halogeno have the previously-given meaning, thienyl, e.g. Z-thienyl and the like, furyl, e.g. 2-furyl and the like, or any other heterocyclic aryl group.

The alkyl portion of an R-lower alkyl radical, which connects the group R with the ring-nitrogen atom, and is represented by (C,,H in the above formula, stands for lower alkylene having from one to three carbon atoms, particularly for methylene, as well as 1,1-ethylene, 1,2- ethylene, l-methyl-l,2-ethylene, 2-methyl-l,2-ethylene or 1,3-propylene and the like.

The substituent R is primarily an aliphatic radical, especially lower alkyl, e.g. methyl, ethyl, npropyl, iso propyl, n-butyl, secondary butyl and the like. It may also stand for a carbocyclic aryl, particularly a monocyclic carbocyclic aryl group, e.g. phenyl or substituted phenyl, such as (lower alkyl) -p'henyl, (etherified hydroxy)-phenyl, particularly (lower alkoXy)-phenyl, (lower alkenyloXy)-phenyl, (lower alkylenedioxy)-phenyl and the like, (esterified hydroxy) -phenyl, particularly (halogeno)-phenyl and the like, (etherified mercapto)-phenyl, particularly (lower alkyl-mercapto)-phenyl and thelike, (nitro)-phenyl, (tertiary amino)-phenyl, particularly (N,N-di-lower .-alkyl-amino)-phenyl, (trifluoromethyl)-phenyl and the like, or any other suitably substituted phenyl group; in these substituted phenyl groups, the substituents have the previously-given meaning. The substituent R may also represent a carbocyclic aryl-aliphatic radical, particularly a monocyclic or bicyclic carbocyclie aryl-lower alkyl radistand for an aliphatic radical, especially lower alkyl, e.g. methyl, ethyl, npropy1, isopropyl, n-butyl, secondary butyl and the like, or any other aliphatic radical.

The hexacyclic carbocyclic aromatic portion of the 2,3,4,5 tetrahydro-lH-1,3-benzodiazepin-4-one nucleus, which in the above formula is represented by the substituted 1,2-phenylene radical Ph, is substituted by one or more than one of the same or of different substituents which may be attached to any of the positions available for substitution. These substituents are particularly aliphatic hydrocarbon, such as lower alkyl, e.g. methyl, ethyl, n-propyl, isopropyl and the like, lower alkenyl, e.g. allyl, Z-methyl-allyl and the like, etherified hydroxyl, particularly lower alkoxy, e.g. methoxy, ethoxy, n-proipyloxy, isopropyloxy, n-butyloxy and the like, lower alkenloxy, e.g. vinyloxy, allyloxy and the like, or lower alkylenedioxy, e.g. methylenedioxy and the like, esterified hydroxyl, particularly halogeno, e.g. fluoro, chloro, bromo and the like, etherified mercapto, particularly lower alkyl-mercapto, e.g. methylmercapto, ethylmercapto and the like, nitro, tertiary amino, particularly N,Ndi-lower alkyl-amino, e.g. N,N-dirnethylamino, N,N-diethylamino and the like, trifiuoromethyl or any other suitable substituent. The substituted 1,2-phenylene group Ph in the above formula may, therefore, be represented by (lower alkyl)-1,2-phenylene, e.g. 3-methyl-l,2-phenylene, 4,5-dimethyl-1,2-phenylene, 4-ethyl-l,2-phenylene, 3-isopropyl-1,2-phenylene and the like, (lower alkenyl)-1,2-phenylene, e.g. 3-allyl- 1,2-phenylene and the like, (etherified hydroxy)-1,2-phenylene, such as (lower alkoxy)-l,2-phenylene, e.g. 3-methoxy-l,2-phenylene, 4,5-dimethoxy-1,2-phenylene, 3,6-dimethoxy-1,2-phenylene, 4,5-diethoxy-1,Z-phenylene, 3-npropyloxy 1,2-phenylene, 4-isopropyloxy-1,2-phenylene and the like, (lower alkenyloxy)-1,2-phenylene, e.g. 3-

vinyloxy-1,2-phenylene, 3-allyloxy-l,Z-phenylene, 4-allyloxy1,2-phenylene and the like, (lower alkylenedioxy)-1,2- phenylene, e.g. 4,5-methylenedioxy-1,2-phenylene and the like, (esterified hydroxy)-l,2-phenylene, particularly (halogeno)-l,2-phenylene, e.g. 3-fiuoro-l,2-phenylene, 3- chloro 1,2-phenylene, 4-chloro-1,2 phenylene, 4,5-dichloro-1,2-phenylene, 3,6-dich1oro-1,2-phenylene, 3-bromo-l,2-phenylene, 4,5-dibromo-1,2-phenylene and the like, (etherified mereapto)-1,2-phenylene, particularly (lower alkyl-mercapto)-l,2-phenylene, e.g. S-methylmercapto-l,2-phenylene, 4-ethylmercapto-l,2-phenylene and the like, (nitro)-l,2-phenylene, e.g. 3-nitro-1,2-phenylene, 4-nitro-1,2-phenylene and the like, (tertiary amiuo)-1,2- phenylene, particularly (N,N-di-lower alkyl-amino)-1,2- phenylene, e.g. 3N,N-dimethylamino-1,2phenylene, 4- N,N-diethylamino-1,2-phenylene and the like, (trifluoromethyl)-1,2-phenylene, e.g. 4-trifluoromethyl-1,2-phenylene and the like, or any other suitably substituted 1,2- phenylene radical.

Salts of the compounds of this invention are particularly pharmacologically and therapeutically acceptable, nontoxic acid addition salts with an inorganic acid, e.g. hydrochloric, hydrobromic, nitric, sulfuric, phosphoric acids and the like, an organic carboxylic acid, e.g. acetic, propionic, glycolic, lactic, pyruvic, oxalic, malonic, succinic, maleic, hydroxymaleic, dihydroxymaleic', fumaric, malic, tartaric, D-tartaric, citric, benzoic, cinnamic, mandelic, salicylic, 4-aminosalicylic, 2-phenoxybenzoic, 2-acetoxybenzoic acid and the like, or an organic sulfonic acid, e.g. methane sulfonic, ethane sulfonic, 2-hydroxyethane sulfonic, ethane 1,2-disulfonic, p-toluene sulfonic acid and the like. Salts which are primarily used for identification purposes are particularly those with acidic organic nitro compounds, e.g. picric, picrolonic, flavianic acid and the like, or with metal complex acids, e.g. phosphotungstic, phosphomolybdic, chloroplatinic, Reinecke acid and the like.

Also included within the scope of this invention are the N-oxides of the l-R-lowe-r -alkyl-3-R -5-R -2,3,4,5-tetrahydro-lH-1,3-benzodiazepin-4-ones and the pharmacologically and therapeutically acceptable, non-toxic acid addition salts of such N-oxides, particularly those with the above-mentioned acids.

Quaternary ammonium derivatives of the compounds of this invention are particularly those with reactive esters formed by hydro'xylated compounds with strong acids, particularly those with lower alkyl halides, e.g. methyl, ethyl, n-propyl or isopropyl chloride, bromide or iodide and the like, phenyl-lower alkyl halides, e.g. benzyl or 2- phenylethyl chloride, bromide or iodide and the like, dilower alkyl sulfates, e.g. dimethyl sulfate, diethyl sulfate and the like, lower alkyl lower alkane sulfonates, e.g. methyl or ethyl methane sulfonate or ethane sulfonate and the like, or lower alkyl aryl sulfonates, e.g. methyl p-toluene sulfonate and the like. Also included as quaternary ammonium compounds are the quaternary ammonium hydroxides, and the salts obtained by reacting such quaternary ammonium hydroxides with inorganic or, particularly, with organic acids, such as with the salts described hereinbefore as being suitable for the preparation of acid addition salts.

Compounds of this invention may have one or more than one asymmetric center and can, therefore, be present in the form of racemates or optically active antipodes.

The compounds of this invention have tranquilizing and sedative properties and may be used accordingly, for example, in states of overactiveness and excitement, particularly in connection with mental disturbances and disorders, or as calming agents in the treatment of overactive and panic-proned animals.

Particularly useful as tranquilizing compounds are those of the formula in which R represents phenyl, (halogeno)-phenyl or (lower alkoxy)-phenyl, the letter n stands for one of the numbers 1, 2 and 3, R represents lower alkyl, and Ph stands primarily for an (etherified hydroXy)-l,2-phenylene radical, particularly a (lower alkoxy)-1,2-phenylene radical, as well as a (lower alkylenedioxy)-l,2-phenylene or a (lower alkenyloxy)-l,2-phenylene radical, or a (lower alkyl)-1,2-phenylene or a (halogeno)-1,2-phenylene radical, or pharmacologically acceptable, non-toxic acid addition salts thereof.

The compounds of this invention may be used in the form of pharmaceutical preparations, which contain the new compounds in admixture with an organic or inorganic, solid or liquid carrier suitable for enteral 0r parenteral administration. For making up the preparations there can be employed substances which do not react with the active ingredient, such as water, gelatine, lactose, starches, stearic acid, magnesium stearate, stearyl alcohol, talc, vegetable oils, benzyl alcohols, gums, polyalkylene glycols or any other known carrier used for pharmaceutical preparations. The latter may be in the solid form, for example, as capsules, tablets, dragees and the like, or in liquid form, for example, as solutions, suspensions, emulsions and the like. If desired, they may contain auxiliary substances, such as preserving, stabilizing, wetting, emulsifying agents and the like, salts for varying the osmotic pressure, buffers, etc. They may also contain, in combination, other pharmacologically useful substances.

The compounds of this invention may be prepared, for example by reacting an a-[Z-(R-lower alkyl-amino)- phenylJ-a-R -acetic acid N-R -amide, in which the phenyl group carries additional substituents, and R, R and R have the previously-given meaning, with formaldehyde or aformaldehyde-furnishing compound, and, if desired, converting a resulting salt into the free compound,

and/or, if desired, converting a resulting free compound into a salt, an N-oxide or a quaternary ammonium compound thereof, and, if desired, separating a mixture of isomers into the single isomers.

The above reaction is preferably carried out at an elevated temperature and in the presence of an inert solvent, such as, for example, diethylene glycol dimethylether, N,N-dimethylformamide and the like. Formaldehyde may be added in an aqueous solution; it may also be used in the form of a reactive polymer thereof, e.g. trioxymethylene, paraformaldehyde and the like, or an acetal with a lower alkanol thereof, e.g. dimethoxymethane, diethoxymethane and the like, or of any other formaldehyde-furnishing substance, e.g. hexamethylene tetramine and the like. If necessary, the reaction may be performed in a closed vessel and/or in the atmosphere of an inert gas, e.g. nitrogen and the like.

The starting materials used in the above procedure may be prepared, for example, by converting in an Ot-(2 amino-phenyl)-a-R -acetic acid N-R -amide, in which the phenyl radical is further substituted, the amino group into an R-lower alkyl-amino group, in which R has the previously-given meaning, and, if desired, converting a resulting salt into the free compound, and/ or, if desired, converting the free compound into a salt thereof.

The conversion of the free amino group into the R-lower alkyl-amino group is carried out according to known methods, for example, by alkylation using a reactive ester of an R-lower alkanol with a strong acid; such reactive ester is, for example, an R-lower alkyl halide, e.g. chloride, bromide and the like, or an R-lower alkyl sulfonate, e.g. an R-lower alkyl p-toluene sulfonate and the like.

The preferred method for the conversion of the amino group of the starting material into the desired R-lower alkyl-amino group comprises reacting the a-(2-aminophenyl)-ot-R -acetic acid N-R -amide, in which phenyl carries additional substituents, and R and R have the previously-given meaning, with an R-lower alkanal, in which R has the previously-given meaning, and removing in the resulting u-[2-(R-lower alkylidene-amino)-phenyl]-u-R -acetic acid N-R -amide, in which phenyl carries additional substituents, and R, R and R have'the previously-given meaning, the Schitf-base C=N-double bond. The reaction of the amino-compound with the R-lower alkanal (for example, benzaldehyde, phenylacetaldehyde and the like) is carried out by contacting the two reagents, preferably in the presence of an inert solvent, e.g. diethyleneglycol dimethylether and the like, and at an elevated temperature. The removal of the Schiifbase type double bond is performed according to known reduction procedures, for example, by catalytic hydrogenation, or more especially, by treatment with a suitable light metal hydride, particularly a borohydride, e.g. sodium borohydride and the like, in the presence of a suitable inert solvent, e.g. methanol, ethanol and the like.

The starting material, i.e. ot-[2-(R-lower alkyl-amino)- phenyl]-o:-R -acetic acid N-R -amides, used in the reaction of this invention and the Schiff-base type intermediate used for its preparation, i.e. the ot-[2-(R-lower alkylidene-amino)-phenyl]-ot-R -acetic acid N-R -amides, in which compounds phenyl carries additional substituents, and R, R and R have the previously-given meaning, and salts of these compounds are new and are intended to be included within the scope of this invention. These compounds have the formulae in which Ph, R, R R and n have the previously-given meaning, and are more especially represented by the formulae in which Ph', R, R and n have the previously-given meaning; salts of these compounds are acid addition salts, particularly those with inorganic mineral acids.

The compounds of this invention (including the N- oxides) may be obtained in the form of the free bases or as the acid addition salts thereof. A salt may be converted into the free base, for example, by reaction with an alkaline reagent, such as an alkali metal hydroxide, e.g. lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, an alkali metal carbonate or hydrogen carbonate, eg sodium carbonate, potassium hydrogen carbonate and the like, ammonia and the like, or an anion exchanger, etc. A free base may be converted into its pharmacologically useful acid addition salts by reaction with one of the acids outlined hereinbefore, for example, by treating a solution of the base in an inert solvent or solvent mixture with the acid or a solution thereof. The salts may also be obtained as the hemihydrates, monohydrates, sesquihydrates or polyhydrates depending on the conditions used in the formation of the salts.

N-oxides of the compounds of this invention may be prepared by reacting a solution of the l-R-lower alkyl-3- R -5-R -2,3,4,5-tetrahydro-1H-1,3-benzodiazepin 4 one compound in an inert solvent with an N-oxidizing reagent; suitable reagents are, for example, hydrogen peroxide, persulfuric acid or, more especially, organic peracids, e.g. peracetic, perbenzoic, monoperphthalic, p-toluene persulfonic acid and the like. The reaction is preferably carried out at a low temperature, and care has to be taken that the oxidation does not proceed further than intended.

The quaternary ammonium derivatives of the compounds of this invention may be obtained, for example, by reacting the tertiary base With an ester formed by a hydroxylated compound and a strong inorganic or organic acid, particularly with a lower alkyl halide, e.g. methyl, ethyl, n-propyl, isopropyl or n-butyl chloride, bromide or iodide and the like, a phenyl-lower alkyl halide, e.g. benzyl bromide, Z-phenyl-ethyl chloride and the like, a di-lower alkyl sulfate, e.g. dimethyl sulfate, diethyl sulfate and the like, a lower alkyl lower alkane sulfonate, e.g. methyl methane sulfonate and the like, or a lower alkyl aryl sulfonate, e.g. methyl p-toluene sulfonate and the like. The quaternizing reaction is performed in the absence or presence of a solvent, if necessary, while cooling or at an elevated temperature, in a closed vessel under pressure, and/ or in the atmosphere of an inert gas, e.g. nitrogen.

Quaternary ammonium compounds obtained may be converted into the corresponding quaternary ammonium hydroxides, for example, by reacting a quaternary ammonium halide with silver oxide, or a quaternary ammonium sulfate with barium hydroxide, by treating a quaternary ammonium salt with an anion exchanger, or by electrodialysis. From a resulting quaternary ammonium hydroxide there may be prepared quaternary ammonium salts by reacting it with acids, for example, with those outlined hereinbefore for the preparation of the acid addition salts, or with mono-lower alkyl sulfates, e.g. methyl sulfate, ethyl sulfate and the like. A quaternary ammonium compound may also be converted directly into another quaternary ammonium salt without the formation of the quaternary ammonium hydroxide; for example, a quaternary ammonium iodide may be treated with freshly prepared silver chloride to yield the quaternary ammonium chloride, or a quaternary ammonium iodide may be converted into the corresponding chloride by treatment with hydrochloride acid in anhydrous methanol. Quaternary ammonium compounds may also crystallize as the hydrates.

The invention also comprises any modification of the process wherein a compound obtainable as an intermediate at any stage of the process is used as starting material and the remaining step(s) of the process is(are) carried out, as well as any new intermediates.

In the process of this invention such starting materials are preferably used which lead to final products mentioned in the beginning as preferred embodiments of the invention.

The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Temperatures are given in degrees centigrade.

EXAMPLE 1 A solution of 6.5 g. of u-(2-benzylamino-4,S-dimethoxyphenyl)-acetic acid N-methyl-amide and 2 ml. of a 37 percent aqueous formaldehyde solutionin 60 ml. of diethyleneglycol dimethylether is allowed to stand at room temperature for one hour and is then refluxed for three hours. The solution is evaporated to dryness and the solid residue is recrystallized twice to yield the l-benzyl- 7,8 dimethoxy 3 methyl 2,3,4,5 tetrahydro 1H- l,3-benzodiazepin-4-one of the formula which melts at 154155; yield: 5. g.

The starting material may be prepared as follows: Methyl amine is bubbled through a solution of 30 g. of ethyl a (4,5 dimethoxy 2 nitro phenyl) acetate in 1100 ml. of ethanol for six hours. The reaction vessel is then closed and allowed to stand for four days. 20 g. of the crystalline a-(4,S-dimethoxy-Z-nitrophenyl)-acetic acid N-methyl-amide is filtered o-if, M.P. 175-180 another 4.0 g. is recovered from the filtrate.

A suspension of 6.0 g. of a-(4,5-dimethoxy-2-nitrophenyl)-acetic acid N-methylamide and 0.5 g. of palladium on charcoal percent) in 250 ml. of ethanol is treated with hydrogen under about three atmospheres pressure. After completion of the hydrogenation, the catalyst is filtered off, and the filtrate is evaporated to yield the a-(Z-amino-4,5-dimethoxy-phenyl)-acetic acid N-methyl-amide, which is recrystallized from ethanol, M.P. 149152; yield: 4.2 g.

A solution of 13.5 -g. of a-(2-amino-4,'5-dimethoxyphenyl)-acetic acid N-methyl-amide and 6.4 g. of benzaldehyde in 100 m1. of diethyleneglycol dimethylether is treated on the steam bath for four hours. The solution is evaporated to yield the solid a-(2-benz/alamino-4,5-dimethoxy-phenyl)-acetic acid N-methyl-amide of the formula which is dissolved in methanol and treated with a 2.28 g. of sodium borohydride given to the solution in portions. The reaction mixture is allowed to stand overnight and is then diluted with water. The desired a-(Z-benzylamino-4,S-dimethoxy-phenyl)acetic acid N-methyl-arnide of the formula precipitates, is filtered off and recrystallized from a mixture of benzene and hexane and then from a mixture of ethanol and water, M.P. 82-84; yield: 8.5 g.

EXAMPLE 2 which melts at 140-142.

The starting material may be prepared according to the procedure shown in Example 1 by treating the oc-(Z- amino-4,5-dimethoxy)-acetic acid N-methyl-amide with 4-chloro-benzaldehyde and reducing in the resulting ea- [2 (4-chloro-benzalamino) -4,5-dimethoxy-phenyl] -acetic acid N-methyl-amide of the formula the Schiif base-type double bond by treatment with sodium borohydride; the desired u-[2-(4-chlorobenzylamino)-4,5-dimethoxy-phenyl]acetate acid N-methylamide of the formula ll CHz-C-NH-CH:

H300 IIIH CHzQCl melts at 1091'10.

EXAMPLE 3 A solution of 5.7 g. of a-[2-(4-methoxybenzylamino)- 4,5-dimethoxy-phenyl]-acetic acid N-methyl-amide and 1.5 ml. of a 37 percent aqueous formaldehyde solution in 50 ml. of diethyleneglycol dimethylether is treated as shown in Example 2 to yield 4.4 g. of 1-(4-methoxybenzyl) 7,8 dimethoxy-3-methyl-2,3,4,5-tetrahydro-1H- 1,3-benzodiazepin-4-one of the formula which melts at -l32.

The starting material may be prepared according to the procedure shown in Example 1 by treating the (IL-('2- amino-4,5-dimethoxy)-acetic acid N-methyl-amide with 4-methoxy-benzaldehyde and reducing in the resulting u- [2 (4 methoxy benzalamino)-4,5-dimethoxy-phenyl]- acetic acid N-methyl-amide of the formula the Schitf base-type double bond by treatment with sodium borohydride; the desired a-[2-(4-methoxybenzylamino)- 4,5-dimethoxy-pheny1]-acetie acid N-methyl-amide of the formula H300 CHr-(J-NH-CHB H300 NH dHQ-OQH;

which melts at 104-106 Other compounds, such as, for example,

1-benZyl-7 8-methylenedioXy-3 -ethyl-2, 3 ,4,5-tetr-ahydro- 1H-1,3-benzodiazepin-4 one, 14benZyl-7-ethoxy-3-methyl-2,3 ,4,5-tetrahydro-1H-1,3- benzodiaziepin-4-one, 1-benzyl-7 8-dichloro-3methyl-2,3,4,5-tetrahydro- 1H-1,3-benzodiazepin-4-one, 1-benzy1-3,8-dimethyl-2,3 ,4,5-tetrahydro-1H-1,3-

benzodiazepin-4-one, 1-benzyl-3-methyl-8-nitro-2,3,4,5-tetrahydro-1H-1,3-

benzodiazepin-4-one, 1-benzyl-7,8-dimethoXy-3-pheny1-2,3,4,5-tetrahydro-1H- 1,3-be-nzo diazepin-4-0ne, 7,8-dimethoxy-3-methyl- 1- 2-phenylethyl -2,3,4,5-

tetrahydro-1H-1,3-benZodiazepin-4-one, 1-benzyl-7-fluoro-3,5-dimethyl-2,3 ,4,5-tetrahydro-1H- 1,3-benzodiazepin-4-one, 7-al1yloxy-1-benzyl-3-methyl-2,3,4,5-tetrahydro-1H- 1,3-benzodiazepin-4-one, 1-benzyl-3,7,8-trirnethyl-2,3,4,5-tetrahydro-1H 1;3-

benZodiazepin-4-one, 1- 3 ,4,5-trimethoxy-benzyl -7,8-dimethoxy-3-methyl- 2,3,4,5-tetrahydro-1H-1,3-benzodiaZepin-4-one, 1- (4-methyl-benzyl) -3-methyl-8-trifiuoromethyl- 2,3 ,4,5-tetrahydro-1H-1,3 -benzodiazepin-4-one, 7, 8-dimethoxy3 -methyl-1- l-naphthylmethyl) -2,3,4,5

tetrahydro-1I-I-1,3-benzodiazepin-4-one, 7,8-dimetho-xy-3-methyl- 1- 3-pyridylmethyl -2,3,4,5-

tetrahydro- 1H- 1,3 -benzodiazepin-4-one and the like, are prepared according to the above method by selecting the appropriate starting materials, i.e.

oc- 2-benzylamino-4,S-methylenedioxy-phenyl acetic acid N-ethyl-amide (from 06- (Z-benzalamino-4,5-methylenedioxy-phenyl acetic acid N-ethyl-amide) a-(Z-benzylamino-S-ethoxy-phenyl)-acetic acid N- methyl-amide (from u-(2-benzalamino-S-ethoxy-phenyl) -acetic acid N-methyl-amide),

oc- 2-benzylamino-4,S-dichlormphenyl -acetic acid N-methyl-amide (from u- (Z-benzalamino-4,5-dichloro-pheny1) acetic acid N-methyl-amide) a- Z-benzylamino-4-methyl-phenyl) -acetic acid N-methyl-amide (from a- (2-benzalamino-4-methyl-phenyl) -acetic acid N-methyl-amide),

oc- 2-be1izylamino-4-nitro-phenyl -acetic acid N-methylamide (from a-(2-benzalamino-4-nitro-phenyl)-acetic acid N-methyl-zamide) a- 2-benzylamino-4,S-dimethoxy-phenyl -acetic acid N-phenyl-amide (from a-(2-benzalamin0-4,S-dimethoxy-phenyl) -acetic acid N-phenyl-amide) a- 4,5-dimethoxy- (Z-phenylethylamino -phenyl] -acetic acid N-methylamide (from a-[4,5-dimethoxy-2-(Z phenylethylideneamino) phenyl] -acetic acid N-methyl-amide),

oc- (2-benzylamino-S-fluoro-phenyl -u-methyl-acetic acid N-methyl-amide (from oc- 2-benzalamino-S-fluoro-phenyl) -a-methylacetic acid N-methyl-amide) a-(Z-benzylamino-S-allyloxy-phenyl)-acetic acid N- methyl-amide (from u-(2-benzal-amino-5-allyloxy-phenyl)-acetic acid N-methyl-amide) a- 2-benzylamino-4,S-dimethyl-phenyl -acetic acid N- methyl-amide (from a-(2-benzalamino-4,S-dimethyl-phenyl) -acetic acid N-methyl-amide),

a- [4,5 -dimethoxy-2- 3,4,5 -trimethoXy-benzylamino phenyl] -acetic acid N-methyl amide (from 11- [4,5 -dimethoXy-2- 3,4,5 -trimethoxybenzalamino) -phenyl] -acetic acid N -methyl-amide) a- 2- (4-methyl-benzylamino -4-trifluoromethyl-phenyl] acetic acid N-methyl-amide (from a- 2- 4-methyl-benzal-amino) -4-trifluoromethylphenyl] -acetic acid N-methyl-amide,

oc- 4,5-dimethoXy-2-( l-naphthyl-methylamino -phenyl] acetic acid N-methyl-amide (from a- [4,5-dimeth0xy-2-( 1-napl1thy1methylene)- phenyl] -acetic acid N-methyl-amide, and

a- [4,5 -dimethoxy-2- 3-pyridylmethylamino -phenyl] acetic acid N-methyl-amide (from oz- [4,5 -dimeth oxy-Z- 3-pyridyl-methyleneamino phenyl] acetic acid N-methyl-amide) respectively.

What is claimed is:

1. A member selected from the group consisting of a compound of the formula v in which Ph is a member selected from the group consisting of (lower alkyl) -1,2,-phenylene, (lower alkoxy) -1,2-phenylene, (lower alkenyloXy) -1,2-phenylene, (lower alkylenedioxy)-1,2-phenylene, (halogeno) 1,2-phenylene, (nitro) -1,2-phenylene and (trifiuoromethyl) -1,2-.phenylene in which m stands for one of the integers 1 and 2, R is a member selected from the group consisting of phenyl, (lower alkyl) -phenyl, (lower alkoxy) -phenyl, (halogeno) -phenyl, naphthyl and pyridyl in which p as well as It stands for one of the integers -1, 2, and 3, R is a member selected from the group consisting of lower alkyl and phenyl, and R stands for a member selected from the group consisting of hydrogen and lower alkyl, and acid addition salts thereof.

2. A compound of the formula II om-o-NH-rw in which R is phenyl, R stands for lower alkyl, and Ph stands for (lower alkoxy) -l,2-phenylene in which m stands for one of the integers 1 and 2.

3. A compound of the formula o1-ra- NHR,' Ph

\IIIH OH2R in which R is mono-halogenophenyl, R is lower alkyl, and Ph is (lower alkoxy) -l,2-phenylene in which m stands for one of the integers l and 2.

4. A compound of the formula ITIH CH -R in which R is mono-lower alkoxy phenyl, R is lower alkyl, and Ph is (lower alkoxy) -l,2-phenylene in which in stands for one of the integers 1 and 2.

5. 0c (2-benzylamino-4,S-dimethoxy-phenyl) acetic acid N-methyl-amide.

6. a [2 (4 chloro-benzylamino)-4,5-dimethoxyphenyl)-acetic acid N-methyl-amide.

7. oz [2 (4 rnethoxy-benzylamino)-4,5-dirnethoxyphenyl] -acetic acid N-methyl amide.

8. A member selected from the group consisting of a compound of the formula in which Ph is a member selected from the group consisting of (lower alkyl) -l,2-phenylene, (lower alkoxy) 1,2-phenylene, (lower -alkenyloxy) -1,2-phenylene, (lower alkylenedioxy l ,2-phenylene, (halo geno W l ,2-phenylene, (nitro) l,2-phenylene and (trifluOrOmethyD -I, Z-phenylene in which in stands for one of the integers 1 and 2, R is a member selected from the group consisting of phenyl, (lower alkyl) -phenyl, (lower alkoxy) -phenyl, (halogenoh-phenyl, naphthyl and pyridyl in which p as well as It stands for one of the integers 1, 2, and 3, R is a member selected from the group consisting of lower alkyl and phenyl, and R stands for a member selected from the group consisting of hydrogen and lower alkyl, and acid addition salts thereof.

9. A compound of the formula (DH-R in which R is phenyl, R stands for lower alkyl, and Ph stands for (lower alk0Xy) -1,2-phenylene in which m stands for one of the integers 1 and 2.

10. A compound of the formula OHz-ii-NHR{ N ('iHR' in which R is mono-halogenophenyl, R is lower alkyl, and Ph is (lower alkoxy) -1,2-p-henylene in which m stands for one of the integers 1 and 2.

11. A compound of the formula No references cited.

WALTER A. MODANCE, Primary Examiner.

NATALIE TROUSOF, Assistant Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,310,582 March 21, 1967 George de Stevens It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 11, line 29, for "phenyl)" read phenyl] column 12, line 39, after "acetic" insert acid Signed and sealed this 21st day of November 1967.

(SEAL) Attest:

EDWARD J. BRENNER Edward M. Fletcher, Jr.

Commissioner of Patents Attesting Officer 

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF A COMPOUND OF THE FORMULA
 8. A MEMBER SELECTED FROM THE GROUP CONSISTING OF A COMPOUND OF THE FORMULA 